Alzheimer?s disease (AD) is a neurodegenerative dementia that affects about 47 million patients worldwide and has been identified as the sixth-leading cause of death in the United States. There are large unmet needs in the field of drug development of therapeutics for AD. Currently, the success rate for AD drug approval is 0.4%, which is one of the lowest in all therapeutic areas. Therefore, it is mandatory to explore novel drug targets that play functional role in the pathology of AD and that has not been explored previously. Estrogen Related Receptors (ERRs) are members of the nuclear hormone receptors (NRs) superfamily. NRs are ligand-activated transcription factors and the ligands of NRs tend to activate or repress the transcription factors that control several genes involved in many important physiological processes such as metabolism, immunity, inflammation, homeostasis, development, cell growth, and reproduction. The ERRs subfamily comprise three members, ERR?, ERR? and ERR?. They are closely related to the estrogen receptors (ER? and ER?) but unlike ER receptors, ERRs have constitutive activity and can function in absence of ligands. The ERRs are orphan receptors because no natural ligands have been identified for any of the three ERR isoforms. Although ERRs are structurally related to ERs and share sequence similarity with these receptors, they do not bind with estrogens which are the endogenous ER ligands. ERR? is expressed mainly in tissues of high energy demand such as brown adipose tissue, intestine, skeletal muscles, and brain and functions as a sensor of energy metabolism. There is a growing evidence that ERR? is a potential drug target in Alzheimer?s Disease (AD) because of the role it plays in regulating genes involved in oxidative stress and because of its anti-inflammatory properties. Recently, overexpression of ERR? was shown to inhibit the processing of ?-amyloid precursor protein (APP) and reduce phosphorylation of Tau in HEK/APP cells, both under normal conditions and under oxidative stress. ERR? is regulated by energy status in the brain and clinical dementia is strongly associated with attenuation in energy metabolism. Therefore, ERR? could also play role in the pathology of dementia. ERR? is known to be highly intractable as a drug target. The progress in drug development for ERR? is limited to the development of inverse agonists. The goal of this research project is to identify ERR? selective agonists and develop these agonists to be used as chemical probes to validate ERR? as a putative target for the treatment of Alzheimer?s Disease. To achieve this goal, we propose the following Aims: 1) Design and synthesis of small molecule ERR? selective agonists based on our preliminary discovery. 2) Pharmacological and pharmaceutical characterization of synthesized ERR? agonists in vitro and in vivo where we will assess the efficacy of developed ERR? agonist in ameliorating AD-like pathology in vitro.